In 1989 a possible paramyxovirus etiology for giant cell hepatitis was proposed, based on electron micrographic changes seen in the livers of patients with this disease. Attempts to transmit the disease to primates have been initiated. Patients with thalassemia in Sardinia, Italy, receive monthly blood transfusions as therapy. Many of these patients have developed chronic hepatitis of unknown etiology. These patients are being studied for evidence of previously unrecognized hepatitis viruses. Similarly, clinical samples from patients with acute or chronic non-A, B, C, D, E hepatitis in the United States are being studied for biological, serological or molecular evidence of transmissible agents. Patients with fulminant non-A, non-B hepatitis remain a diagnostic enigma and may be infected with one or more previously unrecognized viruses. We are attempting to transmit the disease to primates. Evidence for the existence of an additional water-borne hepatitis virus has come from sero-epidemiologic studies in India and Saudi Arabia. From 50-100% of hepatitis cases in sixteen epidemics of water-borne hepatitis were caused by HEV but 1 water-borne epidemic was caused by neither HAV nor HEV. Similarly, in Saudi Arabia, 13.4% of acute hepatitis in adults could not be diagnosed as hepatitis A-E and appeared to be transmitted by nonparenteral means. Some years ago, a hepatitis virus was reported to be transmissible from a non-A, non-B hepatitis patient to marmoset monkeys. The agent, called the GB agent, could be serially transmitted in marmosets and was partially characterized. Recently the GB agent was cloned and sequenced and shown to be distantly related to a previously unrecognized human virus. Others have independently discovered an additional human virus. The GB agent and the newly discovered human viruses are being studied in primates and in vitro. The objectives of this project are to identify and characterize new etiologic agents of hepatitis and to develop useful assays for diagnosis of infection and seroepidemiologic studies. A long-term objective is the development of passive and active immunoprophylaxis for these human pathogens.